The overall objective of the study is to evaluate the effect of treatment with filgotinib on the induction and maintenance of clinical remission, as well as , endoscopic response in subjects with moderately to severely active Crohn's disease (…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy will be assessed by CDAI and SES-CD (co primary):
• Clinical remission by CDAI is defined CDAI < 150
• Endoscopic response is defined as SES-CD score (based on central reading)
reduction of >= 50% from baseline
In the EU, primary efficacy will be assessed by PRO2 and SES-CD (co-primary):
• Clinical remission by PRO2 is defined as abdominal pain score <= 1 1 (on a
scale of 0 to 3) AND stool frequency <= 3.
• Endoscopic response is defined as SES-CD score (based on central reading)
reduction of >= 50% from baseline
Secondary outcome
See objectives of the study
Background summary
A significant change in CD management and therapeutic strategy has occurred
over the last decade. Recent therapeutic goals extend beyond symptomatic
control and include long-term mucosal and endoscopic remission. The ultimate
aim is to change the natural course of the
disease by slowing down or halting its progression, thus avoiding surgery or
hospitalization. This is believed to be achieved by utilizing earlier,
aggressive, and goal-directed therapy. Risk assessment and prediction by means
of complex clinical, biochemical, and endoscopic markers
has become the key to patient management, therapy optimization, and prediction
of the outcome and side effects of medical therapy. Many new treatments focus
on inhibiting, suppressing, or altering T-cell differentiation and homing.
Three monoclonal antibodies which inhibit tumor
necrosis factor-alpha (TNFα), are currently marketed for the treatment of CD:
infliximab (Remicade®), adalimumab (Humira® [approved in US and European Union
{EU}]) and certolizumab pegol (Cimzia® [approved in US]). More recently,
vedolizumab (Entivyo® [approved in US and EU]), a monoclonal antibody against
α4β7 integrin was approved by US Food and Drug Administration (FDA) and
European Medicines Agency (EMA). Other approaches include the administration of
cytokines to stimulate innate immunity and the use of prebiotics to alter the
gut flora. Blocking the interleukin (IL)-6 signaling pathway is also considered
a possible therapeutic strategy for CD: tocilizumab (RoActemra®), an anti-IL-6R
monoclonal antibody (mAb), showed promising results in an early pilot study
{Ito 2004} and a Phase 2 study is currently ongoing with the anti-IL-6 mAb
PF-04236921. In addition, an oral antisense oligonucleotide (GED-0301) is being
evaluated for the treatment of CD showed
encouraging results in a Phase 2 study. Other new treatments being tested in
clinical trials includes janus kinase (JAK) inhibitors (eg, upadacitinib,
tofacitinib), IL-12/23 antagonist (ustekinumab [Stelara]), and a matrix
metallopeptidase-9 (MMP-9) inhibitor (GS-5745).
Leukocytapheresis therapy may be used in Japan. {Fukunaga 2012}.
Despite currently available therapies, long-term or durable remission rates are
still low at approximately 20%. Furthermore, the risk of infection, and in rare
cases malignancy, limits the long-term use or use in vulnerable populations
(eg, children and those with comorbid disorders).
Therefore, a need still exists for safer and durable efficacious therapies for
moderately to severely active CD.
Study objective
The overall objective of the study is to evaluate the effect of treatment with
filgotinib on the induction and maintenance of clinical remission, as well as ,
endoscopic response in subjects with moderately to severely active Crohn's
disease (CD). Subjects who are biologic-naïve or biologic experienced will be
enrolled in Cohort A and subjects who are biologic-experienced will be enrolled
in cohort B, respectively. Treatment assignments will be randomized within each
Cohort.
Cohort A: Biologic-Naïve and Biologic-Experienced Subjects, Induction Study
The primary objectives of Cohort A Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by Crohn's Disease Activity Index (CDAI) at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 10
The key secondary objectives of Cohort A Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by Patient Reported Outcomes (PRO2) at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical response by CDAI at Week 10
The other secondary objectives of Cohort A Induction Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the pharmacokinetic (PK) characteristics of filgotinib
Cohort A (European Union [EU]-Specific Objectives): Biologic-Naïve and
Biologic-Experienced Subjects, Induction Study
The EU-specific primary objectives of Cohort A Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by PRO2 at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 10
The EU-specific key secondary objectives of Cohort A Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by CDAI at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
both clinical remission by PRO2 and endoscopic response (combined into a single
endpoint on a patient level) at Week 10
The EU-specific other secondary objectives of Cohort A Induction Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the PK characteristics of filgotinib
Cohort B: Biologic-Experienced Subjects, Induction Study
The primary objectives of Cohort B Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by CDAI at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 10
The key secondary objectives of Cohort B Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by PRO2 at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical response by CDAI at Week 10
The other secondary objectives of Cohort B Induction Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the PK characteristics of filgotinib
Cohort B (EU-Specific Objectives): Biologic-Experienced Subjects, Induction
Study
The EU-specific primary objectives of Cohort B Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by PRO2 at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 10
The EU-specific key secondary objectives of Cohort B Induction Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by CDAI at Week 10
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
both clinical remission by PRO2 and endoscopic response (combined into a single
endpoint on a patient level) at Week 10
The EU-specific other secondary objectives of Cohort B Induction Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the PK characteristics of filgotinib
Maintenance Study
The primary objectives of the Maintenance Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by CDAI at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 58
The key secondary objectives of the Maintenance Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by PRO2 at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical response by CDAI at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
sustained clinical remission by CDAI at Weeks 10 and 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
6-month corticosteroid-free remission by CDAI at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
sustained clinical remission by PRO2 at Weeks 10 and 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
6-month corticosteroid-free remission by PRO2 at Week 58
The other secondary objectives of the Maintenance Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the PK characteristics of filgotinib
Maintenance Study (EU-Specific Objectives)
The EU-specific primary objectives of the Maintenance Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by PRO2 at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
endoscopic response at Week 58
The EU-specific key secondary objectives of the Maintenance Study are:
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
clinical remission by CDAI at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
sustained clinical remission by PRO2 at Weeks 10 and 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
both clinical remission by PRO2 and endoscopic response (combined into a single
endpoint on a patient level) at Week 58
• To evaluate the efficacy of filgotinib as compared to placebo in establishing
6-month corticosteroid-free remission by PRO2 at Week 58
The EU-specific other secondary objectives of the Maintenance Study are:
• To evaluate the safety and tolerability of filgotinib
• To assess the PK characteristics of filgotinib
Study design
These are combined Phase 3 double-blind, randomized, placebo controlled studies
to evaluate the efficacy and safety of filgotinib in the induction and
maintenance of clinical remission, as well as, endoscopic response in subjects
with moderately to severely active CD.
These studies include:
• Screening (Days -30 to -1)
• Randomization (Day 1)
• Blinded Induction Studies (Day 1 to Week 11)
* - Cohorts A and B Week 10 efficacy assessments:
* At Week 10, CDAI and PRO2 to assess clinical remission
* At Week 10, Simple Endoscopic Score for Crohn*s Disease (SES-CD) to assess
endoscopic response
* - Blinded Bridge Phase (Week 10 to 11): Dosing will continue in a blinded
fashion through the end of Week 10 until re-randomization at Week 11
• Re-randomization (Week 11)
* - Subjects in Cohorts A and B who complete the Induction Study and achieve
either clinical remission by PRO2 or endoscopic response by SES-CD at Week 10
will be re randomized into the Maintenance Study at Week 11
* - Subjects who achieve neither clinical remission by PRO2 nor endoscopic
response at Week 10 will have the option to enter a separate,
• Blinded Maintenance Study (Weeks 11 to 58)
• Post-Treatment (PTx) safety assessments
* - Subjects who opt out of the LTE study (GS US 419 3896) will return 30 days
after the last dose of study drug for PTx safety assessments
* - Subjects who complete all procedures per protocol, including the endoscopy,
of the 58-week study will be offered the option to continue into the LTE study
(GS US 419-3896)
* - Subjects who are eligible and opt to participate in the LTE study (GS US
419-3896) can continue into the study without PTx safety assessments.
Intervention
Treatment Regimen (Cohorts A and B Induction Studies)
Subjects who meet protocol eligibility criteria will be assigned to the
respective Cohort and subsequently randomized in a blinded fashion in a 1:1:1
ratio to 1 of 3 treatments as follows:
Treatment 1 (n = 220): filgotinib 200 mg and placebo to match (PTM) filgotinib
100 mg, once daily
Treatment 2 (n = 220): filgotinib 100 mg and PTM filgotinib 200 mg, once daily
Treatment 3 (n = 220): PTM filgotinib 200 mg and PTM filgotinib 100 mg, once
daily
Note: United States (US) males who have not failed at least two prior biologic
therapies (any tumor necrosis factor-alpha [TNF-alfa] antagonist and
vedolizumab) will be randomized in a 1:1 ratio to either filgotinib 100 mg or
matching placebo.
Within each Cohort, treatment assignments will be stratified according to the
following factors in the Induction studies:
Stratification Factors (Cohort A, Biologic-Naïve and Biologic-Experienced
Induction Study)
• History of exposure to no biologic agent, one biologic agent, or more than
one biologic agent
• Concomitant use of oral, systemically absorbed corticosteroids (eg,
prednisone) at Day 1, (Yes or No)
• Concomitant use of immunomodulators (eg, 6 mercaptopurine [6 MP],
azathioprine, methotrexate [MTX]) at Day 1, (Yes or No)
Stratification Factors (Cohort B, Biologic-Experienced Induction Study)
• Exposure to one biologic agent versus more than one biologic agent
• Concomitant use of oral, systemically absorbed corticosteroids (eg,
prednisone) at Day 1, (Yes or No)
• Concomitant use of immunomodulators (eg, 6 MP, azathioprine, MTX) at Day 1,
(Yes or No)
Subjects from Cohort A or B who are eligible for the Maintenance study will be
re-randomized to treatment as follows:
Treatment Assignment Induction Studies Cohorts A and B Maintenance Study
Re-randomization
Treatment 1, filgotinib 200 mg
Treatment 1, 200 mg
Treatment 3, Placebo
Treatment 2, filgotinib100 mg
Treatment 2, 100 mg
Treatment 3, Placebo
Treatment 3, Placebo
Continue Treatment 3, Placebo
Note: Subjects receiving Treatment 1 or 2 in the Induction study will be
randomized in a 2:1 manner to either continue on the assigned filgotinib
regimen or to placebo for the duration of the Maintenance study
Stratification Factors (Maintenance Study)
• History of exposure to a biologic agent (Yes or No)
• Concomitant use of oral, systemically absorbed corticosteroids (eg,
prednisone) at Day 1, (Yes or No)
• Concomitant use of immunomodulators (eg, 6 mercaptopurine [6 MP],
azathioprine, methotrexate [MTX]) at Day 1, (Yes or No)
Study burden and risks
Please refer to the Risks section in the ICF for a full overview of the risks
associated with Filgotinib.
333 Lakeside Drive NA
NA CA 94404 Foster City
US
333 Lakeside Drive NA
NA CA 94404 Foster City
US
Listed location countries
Age
Inclusion criteria
For a complete list of study inclusion and exclusion criteria, please refer to
Section 4. , Main Eligibility Criteria (Cohorts A & B):
All subjects must meet all of the following criteria to be eligible for
participation in either the Cohort A or B Induction Study.
• Males or non-pregnant, non-lactating females, ages 18 to 75 years, inclusive
based on the date of the screening visit
• Documented diagnosis of CD with a minimum disease duration of 3 months with
involvement of the ileum and/or colon at a minimum, documented by the following:
a) Medical record documentation of, or an ileocolonoscopy (full colonoscopy
with the intubation of terminal ileum) report dated >= 3 months before
enrollment, which shows features consistent with CD, determined by the
procedure performing physician, AND
b) Medical record documentation of, or a histopathology report showing features
consistent with CD, determined by the pathologist.
• Moderately to severely active CD determined by CDAI 220 to 450 (inclusive),
AND PRO2 (abdominal pain score >= 2 [on a scale of 0 to 3] OR stool frequency >=
4), AND centrally read SES CD score >= 6 (or >= 4 if disease is limited to the
ileum and/or right colon)
• May be receiving the following drugs (subjects on these therapies must be
willing to remain on stable doses for the noted time):
a) Oral 5-aminosalicylate (5-ASA) compounds provided the dose prescribed has
been stable for at least 4 weeks prior to randomization; dose must remain
stable for the first 10 weeks after randomization
b) Azathioprine or 6-MP or MTX provided the dose prescribed has been stable for
4 weeks prior to randomization; dose must remain stable for the first 10 weeks
after randomization
c) Oral corticosteroid therapy (prednisone prescribed at a stable dose <= 30
mg/day or budesonide prescribed at a stable dose of <= 9 mg/day) provided the
dose prescribed has been stable for 2 weeks prior to randomization; dose must
remain stable for the first 14 weeks after randomization
d) Antibiotics for the treatment of CD (eg, metronidazole, ciprofloxacin)
provided the dose prescribed has been stable for 2 weeks prior to
randomization. Dose must remain stable for the first 10 weeks after
randomization. Subjects who are on cyclic therapy must continue their standard
low-dose regimen without change for the first 10 weeks after randomization.
• Must not have the current following complications of CD:
a) Symptomatic strictures, OR
b) Severe (impassable) rectal/anal stenosis, OR
c) Fistulae other than perianal fistulae, OR
d) Short bowel syndrome, OR
e) Any other manifestation that might require surgery, OR
f) Any other complications which could preclude the use of the CDAI to assess
response to therapy, or would possibly confound the evaluation of benefit from
treatment with filgotinib
• Must not have ulcerative colitis, indeterminate colitis, ischemic colitis,
fulminant colitis, or toxic mega-colon
• Must not have active tuberculosis (TB) or history of latent TB that has not
been treated (see inclusion criterion 7 for further information)
• Must not use any prohibited concomitant medications as described in Section
5.4.2
Cohort A (Biologic-Naïve and Biologic-Experienced) Induction Study
Main Eligibility Criteria, Cohort A ONLY
Subjects must meet all of the additional criteria to be eligible for
participation in Cohort A Induction Study.
Biologic-Naïve Subjects
• Previously demonstrated an inadequate clinical response, loss of response to,
or intolerance of at least one of the following agents (depending on current
country treatment recommendations/guidelines):
a) Corticosteroids
i) Active disease despite a history of at least an induction regimen of a dose
equivalent to oral prednisone 30 mg daily for 2 weeks or intravenously (IV) for
1 week, OR
ii) Two failed attempts to taper steroids below a dose equivalent of 10 mg
daily prednisone, OR
iii) History of steroid intolerance including, but not limited to, Cushing*s
syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, serious
infections, depression, allergic reactions, mood disturbances, or any other
condition that contributed to discontinuation of the agent
b) Immunomodulators
i) Active disease despite a history of at least a 12 week regimen of oral
azathioprine (>= 2 mg/kg/day) or 6-MP (>= 1 mg/kg/day), or MTX (25 mg
subcutaneously [SC] or intramuscularly [IM] per week for induction and >= 15 mg
IM per week for maintenance), OR
ii) History of intolerance to at least one immunomodulator including, but not
limited to, serious infections, hepatotoxicity, cytopenia, pancreatitis,
thiopurine methyltransferase (TPMT) genetic mutation, allergic reactions, or
any other condition that contributed to discontinuation of the agent
• No prior or current use of any TNFα antagonist including (but not limited to)
infliximab, adalimumab, golimumab, certolizumab, or biosimilar agents at any
time
• No prior or current use of vedolizumab at any time
• No prior or current use of ustekinumab at any time
Biologic-Experienced Subjects
• Previously demonstrated an inadequate clinical response, loss of response to,
or intolerance of, at least one of the following agents (depending on current
country treatment recommendations/guidelines) or discontinuation of use of at
least one of the following agents for reasons other than inadequate clinical
response, loss of response, or intolerance:
a) TNFα Antagonists
i) Active disease despite a history of at least one induction regimen of
infliximab, adalimumab, certolizumab or biosimilar as follows:
• Infliximab: A 14-week induction regimen of 5 mg/kg IV at Weeks 0, 2, and 6 (6
week induction regimen with 2 doses at Weeks 0 and 2 in European Union [EU])
• Adalimumab: A 4-week induction regimen consisting of 160 mg SC (four 40-mg
injections in one day or two 40 mg injections per day for two consecutive days)
on Day 1, followed by a second dose 2 weeks later (Day 15) of 80 mg
• Certolizumab: A 8 week induction regimen of 400 mg SC at Weeks 0, 2 and 4
OR
ii) Recurrence of symptoms during maintenance therapy with the above agents, OR
iii) History of intolerance to any TNFα antagonists including, but not limited
to, serious infections, hepatotoxicity, heart failure, allergic reactions, or
any other condition that contributed to discontinuation of the agent
b) Vedolizumab
i) Active disease despite a history of at least a 14 week induction regimen of
vedolizumab consisting of 300 mg IV at Weeks 0, 2 and 6, OR
ii) History of intolerance to vedolizumab including, but not limited to,
serious infections, hepatotoxicity, cytopenia, allergic reactions, or any other
condition that contributed to discontinuation of the agent
c) Ustekinumab
i) Active disease despite a history of a 8 week induction regimen with a single
dose of ustekinumab IV per weight based dosing (260mg for up to 55kg; 390mg for
greater than 55 to 85kg; 520mg for greater than 85kg) at Week 0, OR
ii) Recurrence of symptoms during maintenance therapy with ustekinumab SC, OR
iii) History of intolerance to ustekinumab including, but not limited to,
serious infections, allergic reactions, or any other condition that contributed
to discontinuation of the agent
• Must not have used any TNFα antagonist or vedolizumab <= 8 weeks prior to
screening, ustekinumab IV or SC <=12 weeks prior to screening, or any other
biologic agent <= 8 weeks prior to screening or within 5 times the half life of
the biologic agent prior to screening, whichever is longer. Subjects who have
an undetectable serum level of a biologic agent since its last dose using a
commercially available assay can undergo study screening without the
above-mentioned waiting period.
Cohort B (Biologic-Experienced) Induction Study
Main Eligibility Criteria, Cohort B ONLY
• Previous
Exclusion criteria
See above Main Eligibility Criteria
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001367-36-NL |
| ClinicalTrials.gov | NCT02914561 |
| CCMO | NL59096.041.17 |